Kollicoat Emm 30 D

Technical Information

Kollicoat® EMM 30 D

August 2004 Supersedes issue dated January 2004 MEMP 030723e-02/Page 1 of 12

® = Registered trademark of BASF Aktiengesellschaft

Ethyl acry­late-­methyl methac­ry­late copol­ymer for sus­tained-­release phar­ma­ceu­ti­cal for­mu­la­tions

Excipients s Contract Manufacturing Value Added

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Kollicoat® EMM 30 D

Contents Page

1 Introduction

3

1.1 General Information

3

1.2 Chemical structure

3

1.3 Trivial names

3

1.3 Commercial formulation

3

2 Specifications and properties

3

2.1 Description

3

2.2 Physical and chemical properties

3

2.3 Pharmacopoeias

4

3 Application and processing

4

3.1 Processing notes

4

3.2 Propranolol sustained-release pellets

6

3.3 Ibuprofen sustained-release pellets

8

3.4 Pro­duc­tion of caf­feine sus­tained-­release gran­ules

9

3.5 Gen­eral notes for the pro­duc­tion of a spray sus­pen­sion

10

3.6 Additional applications

10

4 Storage

11

5 Stability

11

6 PBG No.

11

7 Packaging

11

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Kollicoat® EMM 30 D

1 Introduction 1.1 General Information

Kol­li­coat® EMM 30 D is a copol­ymer based on ethyl acry­late and ­methyl methac­ry­late. It has a neu­tral char­ac­ter. The poly­mer is suit­able for the pro­duc­ tion of sus­tained-­release for­mu­la­tions and trans­der­mal ther­a­peu­tic ­systems. It has a ­strong, pH-inde­pen­dent sus­tained-­release ­effect. More­over, it can also be used for taste mask­ing.

1.2 Chemical structure



The ratio of ethyl acry­late : ­methyl methac­ry­late is approx­i­mately 2 : 1. Kol­li­coat® EMM 30 D is a neu­tral ester dis­per­sion with­out func­tional ­groups. The aver­age molec­u­lar ­weight is approx­i­mately 800,000.

1.3  Triv­ial names

Poly­ac­ry­late dis­per­sion 30% (Ph. Eur.), Ethyl Acry­late-­Methyl Methac­ry­late Copol­ymer Emul­sion (JPE)

1.4  Com­mer­cial for­mulation

Kol­li­coat® EMM 30 D is an aque­ous dis­per­sion with a 30% sol­ids con­tent. The ­cloudy white, low-vis­cos­ity prod­uct has a weak, char­ac­ter­is­tic odour.

2 Specifications and properties 2.1  Descrip­tion

The dis­per­sion con­tains 1.5% Non­oxy­nol 100 as an emul­si­fier. Kol­li­coat® EMM 30 D is a neu­tral ester dis­per­sion which forms water-insol­u­ble films.

2.2 Phys­i­cal and chem­i­cal prop­er­ties

Iden­tity:

­passes test

Film for­ma­tion:

­passes test

Sol­u­bil­ity:

­passes test

Rel­a­tive den­sity:

1.037–1.047

Vis­cos­ity:

max. 50 mPas

Coag­u­late con­tent:

max. 0.5%

Sol­ids con­tent:

28.5–31.5%

Sul­phated ash:

max. 0.2%

Heavy met­als:

max. 20 ppm

Arsenic:

max. 2 ppm

Monomers:

max. 100 ppm

Micro­bial ­status:

­passes test

Sol­u­bil­ity Kol­li­coat® EMM 30 D can be mixed with water in any pro­por­tion while retain­ing its ­cloudy white appear­ance. Mix­ing the prod­uct with ace­tone, eth­a­nol or iso­propyl alco­hol at a ratio of 1 : 5 ­results in a ­weakly opal­es­cent, vis­cous solu­tion. When ­organic sol­vents are added, the poly­mer ­initially pre­cip­i­tates out; how­ever, it redis­solves on addi­tion of more sol­vent. Kol­li­coat® EMM 30 D is not sol­u­ble in ­diluted alka­line solu­tions. The ­cloudy white appear­ance of the dis­per­sion is pre­served. Film for­ma­tion When the prod­uct is ­poured out onto a glass plate, a clear film is ­formed after evap­o­ra­tion of the water. Vis­cos­ity Vis­cos­ity is deter­mined accord­ing to DIN EN ISO 3219 at a shear rate of 250 s-1 and 23 °C.

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Kollicoat® EMM 30 D

Coag­u­late con­tent 100 g of the sub­stance is fil­tered ­through a 90 µm ­screen. The res­i­due is dried to con­stant ­weight in the dry­ing cab­i­net at 105°. Micro­bial ­status The test of micro­bial ­status is car­ried out accord­ing to Ph. Eur., Cat­e­gory 3. If not spec­i­fied oth­er­wise, the deter­mi­na­tion meth­ods are taken from the current Euro­pean Phar­ma­co­poeia. 2.3  Phar­ma­co­poeias Kol­li­coat® EMM 30 D meets the require­ments of the mono­graph Poly­ac­ry­late Dis­per­sion 30% (Ph. Eur.) and Ethyl Acry­late-­Methyl Methac­ry­late Copol­ymer Dis­per­sion (JPE).

3.  Appli­ca­tion and pro­cess­ing 3.1  Pro­cess­ing notes Cer­tain exter­nal fac­tors can cause aque­ous dis­per­sions to coag­u­late, ren­der­ing them unfit for use. These fac­tors are: •  The addi­tion of ­finely dis­persed pig­ments •  High shear gra­dients when stir­ring and grind­ing •  The addi­tion of emul­si­fi­ers, stab­il­is­ers, or wet­ting ­agents •  Changes in pH • ­ Organic sol­vents •  Foam for­ma­tion Foam for­ma­tion dur­ing pro­cess­ing can be pre­vented by add­ing a sil­i­cone anti­ foam such as Phar­sil 21046. Kol­li­coat® EMM is a soft poly­mer, which makes the use of a plas­ti­cizer unnec­es­sary. The prod­uct forms very flex­ible, exten­sible films. Cores con­tain­ing sub­stances that are water-sen­si­tive or incom­pat­ible with the sus­tained ­release coat­ing ­should first be given a sub­coat­ing. A coat­ing ­weight of 0.2–2.0 mg/cm2 is ­required, depend­ing on the poly­mer used. A sub­coat­ing film of an ­organic solu­tion is rec­om­mended for water-sen­si­tive ­active ingre­dients. Kol­li­don® VA 64 is sug­gested as a poly­mer for a sub­coat­ing. It is rec­om­mended to sub­se­quently dry the pel­lets. If the pel­lets, gran­ules or crys­tals are sur­rounded by a non­por­ous mem­brane, very effec­tive sus­tained-­release is ­achieved. In order to ­adjust the ­release char­ac­ ter­is­tics of the ­active ingre­dients in sus­tained-­release forms, addi­tions of pore-form­ing ­agents are nec­es­sary. The best con­trol can be ­achieved with water-sol­u­ble poly­mers or ­slightly swell­ing water-insol­u­ble poly­mers. The perme­abil­ity of the water-insol­u­ble films can be var­ied •  by the thick­ness of the coat­ing • by the use of pore-form­ing ­agents (HPMC, micro­crys­tal­line cel­lu­lose PH 105). The quan­tity ­depends on the ­release pro­file ­desired. The layer thick­ness ­should not fall below 1.5 mg/cm2 ( approx­i­mately 15 µm), since oth­er­wise film ­defects and bursting may be ­expected. Kol­li­coat® EMM 30 D is a poly­mer with rel­a­tively high tack. Aux­il­iary ­agents are nec­es­sary to ­reduce the tack and to ­improve pro­cess­ing when it is pro­cessed as a coat­ing. Pre­vi­ously, talc was gen­er­ally used for this pur­pose. More ­recent stud­ies have shown that the use of fine micro­crys­tal­line cel­lu­lose or hydrox­y­pro­pyl meth­yl­cel­lu­ lose can ­greatly ­reduce the tack. At the same time, the inlet air tem­per­a­ture and the spray­ing rate can be ­increased, which makes it pos­sible to notice­ably accel­ er­ate the coat­ing pro­cess. At the same time, these sub­stances have the advan­ tage that they can also act as a pore-form­ing agent and give ­stable ­release char­ ac­ter­is­tics through­out the stor­age time.

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Kollicoat® EMM 30 D

The for­mu­la­tions with micro­crys­tal­line cel­lu­lose and HPMC indi­cated in the exam­ples are ­intended as start­ing for­mu­la­tions for devel­op­ing for­mu­la­tions. BASF typ­i­cal for­mu­la­tions Com­po­si­tions of the spray sus­pen­sions Kol­li­coat® EMM 30 D (solids) [%]

Micro­crystal­line cel­lu­lose PH 105 [%]

7.50

7.50

4.50

1

Sparingly soluble active ingredients (< 1%), low tack

2

Sparingly soluble to soluble active ingredients (< 10% solubility)

see 3.3 see 3.4

9.75

3

Soluble to readily soluble active ingredients (> 10%)

see 3.2

11.80

4

Readily soluble active ingredients (> 20%) – strong sustained-release effect

HPMC (Phar­ma­coat® 603) [%]

Tal­c [%] 3.50

0.75

3.50

0.75

6.00

12.50

12.50





Influence of various auxiliary agents on release control and tack  For­mu­la­tion No. 2 is the most suit­able because of its very low tack. The spray­ing con­di­tions ­depend on the for­mu­la­tions and the equip­ment. Nor­mally, the tem­per­a­ture set­tings are as fol­lows: •  Inlet air tem­per­a­ture: 30–65°C •  Out­let air tem­per­a­ture: 20–35°C •  Prod­uct tem­per­a­ture: 20–35°C The min­i­mum film-form­ing tem­per­a­ture (MFT) is less than 10 °C. Ther­mal after­treat­ment (cur­ing) of the ­coated pel­lets is fre­quently unnec­es­sary.

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Kollicoat® EMM 30 D

3.2 Pro­pran­o­lol sus­tained-­­ release pel­lets Com­po­si­tion of the pel­lets: 20% pro­pran­o­lol-HCl, 51.7% Avi­cel® PH 101, 25.8% lac­tose, 2.5% Kol­li­don® VA 64

Com­po­si­tion of the spray sus­pen­sion

The for­mu­la­tion is ­designed for 3 kg pel­lets (diam­e­ter 0.7–1.4 mm) Parts by weight [g]

Proportion [%]

Kol­li­coat® EMM 30 D

895.5

39.3 (11.8 poly­mer)

Phar­ma­coat 603

16.1

0.7

Water

501.2

42.5

Kol­li­don® 30

11.4

0.5

Titan­ium dio­xide

11.4

0.5

Sico­vit® Red 30

11.4

0.5

Tal­c

136.7

6.0

Water

694.3

10.0

2278.0

100.0

Poly­mer­ su­spen­sion ®

Pig­ment s­uspen­sion

Pro­duc­tion of the spray sus­pen­sion

Poly­mer sus­pen­sion:  har­ma­coat® 603 is first added to the spec­i­fied quan­tity of water. P Kol­li­coat® EMM 30 D is added with stir­ring. Pig­ment sus­pen­sion: Kol­li­don® 30 is dis­solved in the spec­i­fied quan­tity of water. ­Sicovit® Red 30, tita­nium diox­ide and talc are added with pow­er­ful stir­ring and homo­gen­ised by means of a corun­dum disc mill. Spray sus­pen­sion: The pig­ment sus­pen­sion is intro­duced into the poly­mer sus­pen­sion with stir­ring. The mix­ture must be ­stirred in order to pre­vent sed­i­men­ta­tion dur­ing the spray­ ing pro­cess.

­Machine param­e­ters

­Machine:

­Hüttlin HKC 5TJ ­coater

Batch size:

3 kg

Inlet air tem­per­a­ture:

45°C

Out­let air tem­per­a­ture:

27°C

Prod­uct tem­per­a­ture:

29°C

Air flow:

320 m3/hr.

Ato­miz­ing pres­sure:

0.6 bar

Spray­ing rate:

38 g/min.

Quan­tity ­applied

3 mg/cm2

Spray­ing time:

60 min.

Afterd­ry­ing:

45°C/3 min.

The spray sus­pen­sion is con­tin­u­ously ­sprayed onto the fluid­ized, pre­warmed pel­lets in the ­Hüttlin ­coater. The above for­mu­la­tion can also be used in fluid­ized-bed coat­ing ­machines. Both the bot­tom spray ­method and the top spray ­method can be used.

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Kollicoat® EMM 30 D

The coat­ing ­weight of 3 mg/cm2 in this case was cal­cu­lated from the sur­face area of the above pel­lets. Since the par­ti­cle size dis­tri­bu­tion and the sur­face struc­ture influ­ence the ­required poly­mer quan­tity, a cal­cu­la­tion of the sur­face area is rec­om­mended in order to esti­mate the quan­tity to be ­applied. The con­cen­tra­tion of pore-form­ing ­agents and tack reduc­ers influ­ence the inlet air tem­per­a­ture and prod­uct tem­per­a­ture that can be used. The ­higher the con­cen­tra­tions of these sub­stances are, the ­higher the cor­re­spond­ing tem­per­a­tures that can be used.



Release of pro­pra­no­lol sustained-release ­pel­lets

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Kollicoat® EMM 30 D

3.3 Ibuprofen sus­tained-­­ release pel­lets Com­po­si­tion of the pel­lets:

60.0% ibu­profen, 2.5% Kol­li­don® VA 64, 37.5% Avi­cel® PH 101 A 70 : 30 sub­coat­ing of 1 mg/cm2 Phar­ma­coat® 603/talc is ­applied to the pel­lets.

Com­po­si­tion of the spray sus­pen­sion

The for­mu­la­tion is ­designed for 2.3 kg pel­lets (* 0.7–1.5 mm) Parts by weight [g]

Proportion [%]

Kol­li­coat® EMM 30 D

540.2

32.50 ( 9.75 poly­mer)

Phar­ma­coat 603

12.5

0.75

Avi­cel PH 105

74.8

4.50

Water

785.2

47.25

Kol­li­don® 30

8.3

0.5

Titan­ium dio­xide

8.3

0.5

Sico­vit Red 30

8.3

0.5

Tal­c

58.2

3.5

Water

166.2

10.0

1662

100.0

Poly­mer­ su­spen­sion ®

®

Pig­ment s­uspen­sion

®

The spray sus­pen­sion is pro­duced by anal­ogy to the pre­vi­ous for­mu­la­tion.

Machine param­e­ters

Machine:

­Hüttlin HKC 5TJ pel­let ­coater

Batch size:

2.3 kg

Inlet air tem­per­a­ture:

48°C

Out­let air tem­per­a­ture:

34°C

Prod­uct tem­per­a­ture:

38°C

Air flow:

375 m3/hr.

Ato­miz­ing pres­sure:

0.6 bar

Spray­ing rate:

28 g/min.

Coat­ing ­weight

2 mg/cm2

Spray­ing time:

60 min.

Dry­ing:

48°C/3 min.

As the ibu­profen pel­lets ­become ­highly ­charged dur­ing coat­ing, the ­coater must be well ­earthed.

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Kollicoat® EMM 30 D

Release of ibu­profen sus­tained-­release pel­lets

3.4 Production of caffeine sus­tained-­­release granules Com­po­si­tion of the spray sus­pen­sion

The for­mu­la­tion is ­designed for 500 g gran­ules (diam­e­ter 0.6–1.8 mm) Parts by weight [g]

Proportion [%]

237.25

32.5

Poly­mer­ su­spen­sion Kol­li­coat® EMM 30 D

(

9.75 poly­mer)

Phar­ma­coat 603

5.48

0.75

Avi­cel PH 105

32.85

4.50

Water

344.92

47.25

Kol­li­don® 30

3.65

0.5

Titan­ium dio­xide

3.65

0.5

Sico­vit Red 30

3.65

0.5

Tal­c

25.55

3.5

Water

73.00

10.0

730.00

100.0

®

®

Pig­ment s­uspen­sion

®

The spray sus­pen­sion is pre­pared in the same way as the pre­vi­ous for­mu­la­tion.

MEMP 030723e-02 August 2004

Machine param­e­ters

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Kollicoat® EMM 30 D

­Machine:

WSG Aero­matic Strea 1, ­Wurster ­insert

Lot size:

500 g

Inlet air tem­per­a­ture:

45 °C

Out­let air tem­per­a­ture:

25 °C

Ato­miz­ing pres­sure:

1 bar

Coat­ing ­weight:

4 mg/cm2

Spray­ing time:

approx­i­mately 60 min includ­ing 3 min. dry­ing time





Release of caf­feine sus­tained-­release gran­ules

3.5 General notes for the production of a spray suspension

Due to the dif­fer­ent sol­u­bil­ities of the ­active ingre­dients and the dif­fer­ent ­release rates they give as a ­result, the ­choice of pore-form­ing agent is very impor­tant in the pro­duc­tion of spray sus­pen­sions. The fig­ures shown in the chart are based on our expe­ri­ence.

3.6  Addi­tional ­applications Kol­li­coat® EMM 30 D can be used as an odour, taste or mois­ture bar­rier, or to pro­tect ­active ingre­dients ­against inter­ac­tion with other sub­stances (pro­tec­tive coat­ing, sub­coat­ing). By gran­u­lat­ing ­active ingre­dients in a fluid­ized bed, for ­instance, and sub­se­ quent com­press­ing, it is pos­sible to pro­duce ­matrix sus­tained-­release tab­lets. The pro­duc­tion of trans­der­mal ­systems is also pos­sible.

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Kollicoat® EMM 30 D

4.  Stor­age

Above freez­ing and not over 30°C.

5.  Stabil­ity

At least 18 ­months in the ­unopened orig­i­nal con­tain­ers at room tem­per­a­ture. Under the ­effects of heat or frost as well as foam­ing, aque­ous dis­per­sions can form coag­u­lates which make them unsuit­able for fur­ther use. Since the prod­uct has a neu­tral pH, care must be taken not to intro­duce con­tam­i­na­tion into the prod­uct, due to the risk of micro­bial ­growth. ­Opened con­tain­ers must be used up as ­quickly as pos­sible, or pre­served with ­sodium hypo­chlor­ite solu­tion (5 ppm ­active chlo­rine).

6.  PBG No.

10 213 678

7.  Pack­ag­ing

25 l poly­eth­y­lene con­tain­ers.

Note The data contained in this publication are based on our current knowledge and experience. In view of the many factors that may affect processing and application of our product, these data do not relieve processors from carrying out their own investigations and tests; neither do these data imply any guarantee of certain properties, nor the suitability of the product for a specific purpose. Any descriptions, drawings, photographs, data, proportions, weights etc. given herein may change without prior information and do not constitute the agreed contractual quality of the product. It is the responsibility of the recipient of our products to ensure that any proprietary rights and existing laws and legislation are observed. August 2004

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BASF Aktiengesellschaft Fine Chemicals Division - Pharma Solutions - 67117 Limburgerhof - www.pharma-solutions.basf.com

Kollicoat® EMM 30 D